Prevalence, outcomes and associated factors of SARS-CoV-2 infection in psoriasis patients of Southwest China: a cross-sectional survey

In this study we aimed to investigate the prevalence of SARS-CoV-2 infection in psoriasis patients, and outcomes of SARS-CoV-2 infection and associated risk factors. A cross-sectional survey was conducted from February 2023 to March 2023. Information was obtained with online questionnaire about psoriasis patients on demographic characteristics, clinical characteristics, SARS-CoV-2 infection and outcomes, vaccination, and routine protection against COVID-19. Logistic regression analysis was used to explore risk factors with SARS-CoV-2 infection and exacerbation of psoriasis. A total of 613 participants were recruited. 516 (84.2%) were infected, and associated factors were sex, working status, routine protection against COVID-19, COVID-19 vaccination, impaired nail, infection exacerbate psoriasis, and severity of psoriasis. Among the patients infected with SARS-CoV-2, 30 (5.8%) required hospitalization, 122 (23.6%) had psoriasis exacerbation due to SARS-CoV-2 infection, and associated factors were subtype of psoriasis, discontinuation of psoriasis treatment during SARS-CoV-2 infection, response following COVID-19 vaccination, and severity of psoriasis. Booster dose vaccination contributed a low probability of COVID-19 sequelae. COVID-19 vaccine’s effectiveness was unsatisfactory, while booster dose vaccination reduced the occurrence of COVID-19 sequelae in psoriasis patients of Southwest China. Patients treated with psoriasis shown to be safe, without a higher incidence of SARS-CoV-2 infection or COVID-19hospitalization compared to untreated patients. Stopping treatment during SARS-CoV-2 infection led to psoriasis exacerbation, so psoriasis treatment could be continued except severe adverse reaction.

biologics and systemic immunosuppressive medication treatment have an increased risk of infection 7 .Nevertheless, Kwee et al. 8 found that biologics or non-biologics systemic therapy did not increase the incidence of SARS-CoV-2 infection.COVID-19 vaccine is an important tool against SARS-CoV-2 infection, with protection effectiveness as high as 95% 9 , but due to breakthrough infection with variants such as Omicron, vaccination with one or more doses only provide 24.7% of effective protection 10 .Regarding psoriasis patients treated with immunosuppressive medications, immunogenicity of the vaccine was impaired and antibody titers decreased 11 .Therefore, real-world studies are required to confirm the effectiveness of vaccine in psoriasis patients confronted with Omicron.
COVID-19 is characterized by excessive host immune response, a cytokine storm due to overproduction of various pro-inflammatory factors such as interleukins (IL) and tumor necrosis factor (TNF), etc 12 , which are common targets for inflammatory diseases such as psoriasis 13 , systematic treatment for these diseases may play a role in COVID-19.Since infection was a trigger factor for psoriasis 14 , there have been case reports about exacerbation or new onset of psoriasis due to SARS-CoV-2 infection 15,16 , but research with large sample sizes and analysis of associated risk factors are lacking.
This study aimed to investigate the prevalence and associated factors of SARS-CoV-2 infection in a realworld setting with psoriasis patients in Southwest China, investigate the factors associated with exacerbation of psoriasis due to SARS-CoV-2 infection, and explore whether psoriasis treatment modalities and vaccination had an impact on COVID-19 to address the above paradoxical issues.

Study design
We conducted a cross-sectional survey in psoriasis patients from three hospital's dermatology departments of Southwest China through online questionnaire.Patients visiting dermatology clinic with a definitive diagnosis of psoriasis were recruited.Informed consents were collected before conducting the survey.Through the Wen-Juan-Xing platform (Changsha Ranxing Information Technology Co., Ltd., Hunan, China), the online survey was distributed and completed.The questionnaire was conducted between February 2023 and March 2023.All the participants could submit the questionnaire only once.Fully replied questionnaire was considered valid.This study was approved by the ethics committee of The First Affiliated Hospital of Chongqing Medical University, Chongqing, China (Ref no: K2023-080).

Questionnaires
The questionnaire included information about demographic and clinical characteristics of psoriasis, SARS-CoV-2 infection and prognosis, protection methods against Covid-19.The severity of psoriasis was self-assessed according to the area of skin lesions or body surface area (BSA), and BSA ≤ 3% was classified as mild psoriasis, BSA > 3% was moderate-to-severe psoriasis.According to China SARS-CoV-2 Infection Treatment Protocol (Trial 10th Edition) 17 , the followings were definite as SARS-CoV-2 infection: positive rapid antigen detection (RAD) test or positive polymerase chain reaction (PCR) test with or without COVID-19 symptoms; participants with COVID-19 symptoms and close contact history with confirmed cases, but did not undergo RAD test or PCR test.Denial of SARS-CoV-2 infection: negative PCR test or RAD test with or without symptoms related to respiratory infection.And other undefined cases.At present, there is no consensus on the definition of COVID-19 sequelae, according to the transition from strict quarantine policy to reopening at the specific period in China, we defined COVID-19 sequelae as persistent COVID-19 symptoms for more than four weeks in this study 18 .

Sample size
According to the estimated infection rate of SARS-CoV-2 in Guangzhou 19 , we presumed that 80% of the patients had been infected with SARS-CoV-2, and about 18 variables were used to explore the risk factors related to SARS-CoV-2 infection.A sample size of 10 times the number of variables was required in the multivariate regression analysis 20 , so 180 participants infected with SARS-CoV-2 were needed.Considering the actual infection rate may exceed 80%, so the minimum sample size was 180/0.8= 225 21 .

Statistical analysis
Continuous variables with normal distribution were expressed as mean ± standard deviation (SD).Student T-test were applied to evaluate the difference between groups.If the continuous variables were not subject to normal distribution, the median (interquartile range) was used, and the difference of two groups were evaluated by Mann-Whitney U test.Categorical variables expressed as counts (percentage), compared using Pearson's chi-square test or Fisher's exact test.For multiple comparisons of chi-square test, pairwise chi-square test was performed by Bonferroni correction for P-value.Binary multivariate logistic regression was used to investigate the factors related to SARS-CoV-2 infection and the factors related to the exacerbation of psoriasis.Adjusted odds ratio and 95% confidence interval were used to express the effect sizes.All data were analyzed with SPSS 26 (IBM, SPSS Statistics 26) and Graphpad Prism 8 (GraphPad Software Inc., USA).P-value ≤ 0.05 was considered statistically significant.

Ethical approval
This study was approved by the ethics committee of The First Affiliated Hospital of Chongqing Medical University, Chongqing, China (Ref no: K2023-080) and the study process was conducted in accordance with the committee's requirements.The research process complied with the Declaration of Helsinki.Informed consents were collected before conducting the survey.

Exacerbation of psoriasis due to SARS-CoV-2 infection
In univariate analysis on correlation of psoriasis exacerbation and SARS-CoV-2 infection, features significantly different between the groups were age, sex, working status, subtype and duration of psoriasis, mental stress exacerbates of psoriasis, treatment of psoriasis, biologics treatment, psoriasis treatment interrupted when COVID-19 infection, exacerbation of psoriasis following COVID-19 vaccination (Table 4, s5, s6).Subsequently, we used adjusted logistic regression analysis, the results were shown in Table 5 and Fig. 2. Compared with other subtypes of psoriasis, psoriasis vulgaris was less likely to be aggregated (aOR = 0.452; 95% CI 0.247-0.826).Patients with discontinuation of anti-psoriasis treatment, flaring-up of psoriasis following COVID-19 vaccination and moderate-to-severe psoriasis were in risk of exacerbation of psoriasis under SARS-CoV-2 infection.

SARS-CoV-2 infection in psoriasis patients with psoriasis treatment
Among patients treated with all kinds of modalities and untreated patients, no difference in the duration of COVID-19, occurrence of sequelae or COVID-19 hospitalization (P > 0.05).In contrast, for biologics, different probability of COVID-19 sequelae occurrence correlated with certain biologics (p = 0.012), by pairwise comparisons, we concluded that the IL-23 inhibitor generated the lowest rate of COVID-19 sequelae compared to the other three biologics (p < 0.0083), which also had the advantage of preventing the deterioration of psoriasis (Table s10-s12).

Discussion
Since the end of the dynamic zero-COVID policy, the incidence of SARS-CoV-2 infection in mainland China was skyrocketing during a short period.A large sample survey 19 predicted that SARS-CoV-2 infection in mainland China would reach 80.7% on the 30th day after the shift of epidemic prevention policy, another regional study 22 predicted the prevalence was 88.5%.Likewise, our study came to a close prediction, which suggests that Chinese psoriasis patients have a comparable incidence of SARS-CoV-2 infection with the general population.
Previous study 23 revealed risk factors for SARS-CoV-2 infection in the general population include advanced age, male gender, etc.In our study, females were more susceptible to SARS-CoV-2 infection than males, however, it was still debatable whether gender affected SARS-CoV-2 infection 24 .SARS-CoV-2 enters the body through angiotensin-converting enzyme 2 (ACE2), and expression level of ACE2 is higher in male than female, theoretically, male should be more susceptible to SARS-CoV-2 infection 25 , whether there is modulation in ACE2 expression of both genders in patients with psoriasis?Further researches are needed to determine whether males with psoriasis are more susceptible to SARS-CoV-2 infection.Patients with impaired nail and moderate-to-severe psoriasis were more likely to be infected, since impaired nail often indicated severe cases of psoriasis 26 , suggesting that psoriasis severity is a predictor of infection risk 7 .Patients with severe psoriasis express high level of interferon (IFN) 27 , which in term promote the expression of ACE2 28 , therefore have a higher risk of contracting SARS-CoV-2.Infection in general was an environmental factor in the exacerbation or triggering of psoriasis 14 , and patients who experienced exacerbation of psoriasis by infection were more likely to be contracted by SARS-CoV-2.
Our analysis came up with an interesting finding.We noticed that COVID-19 vaccine did not offer valid protection in Chinese psoriasis patients, instead it was associated with the occurrence of SARS-CoV-2 infection for possible reasons: (1) Breakthrough infection with the Omicron variant.Omicron was endemic in mainland China around the end of the dynamic zero-COVID policy 29 , it exhibited higher transmissibility and lower susceptibility to neutralizing antibodies induced by vaccine compared to the original strain 3 .At the same time, (2) Lack of routine protection against COVID-19.In our cohort, ratio of routine protection was lower in vaccinated psoriasis patients than in unvaccinated patients.
Our findings and previous studies 31 have reached consensus routine protection against COVID-19 was a protective factor against SARS-CoV-2 infection.Therefore, we suggest that routine protection should not be neglected even under vaccinated status; (3) Low naturally acquired immunity.A study 32 reported that naturally acquired immunity played more crucial roles in preventing infection than vaccination, while under the previous dynamic zero-COVID policy, the general infection rate in China was at a low level, and herd immunity in Chinese population was far from robust compared with other countries 33 ; (4) Whether psoriasis patients were suitable for COVID-19 vaccination remains controversial.No unified conclusion on whether COVID-19 vaccine in psoriasis patients could stimulate valid specific immunity, especially in patients receiving long-term immunosuppressive therapy with impaired humoral response to the vaccine 34 , who constituted the majority of our cohort.The pathogenesis of psoriasis has not been fully elucidated.Until now, the general research supports that the IL-23/T-helper cell type 17 (Th17) axis dominates the inflammation activation process, and various cytokines such as IL-17, TNF, and IL-12 are involved 13 , which intersects with the pro-inflammatory factors induced by SARS-CoV-2 35 .Aram et al. 15 summarized case reports of psoriasis exacerbation due to SARS-CoV-2 infection, but did not investigate factors associated with exacerbation of psoriasis.In our study, patients with moderate-tosevere psoriasis were more prone to undergo exacerbation, which might due to the fact that they bear a stronger basic inflammatory process 27 , and when SARS-CoV-2 superimposed, it further ignited the inflammation process.Discontinuation of treatment can lead to recurrence or exacerbation of psoriasis 36 .Tissue-resident memory (TRM) T cells are involved in the recurrence of psoriasis after treatment discontinuation.TRM cells can be divided into CD4 + and CD8 + subsets, which respectively promote the production of IL-22 and IL-17A, contribute to an inflammatory environment in localized tissues 37 .SARS-CoV-2 infection also caused exacerbation of psoriasis in patients who had exacerbated after previous COVID-19 vaccination, a review 38 even reported new  onset of psoriasis after COVID-19 vaccination.The mechanism might be vaccination activating of both CD4 + and CD8 + T cells, increasing levels of INF-γ, TNF-α, IL-2 and IL-12 39 .Whether psoriasis patients receiving immunosuppressive therapy were at higher risk of SARS-CoV-2 infection and prone to COVID-19 adverse events remains unsolved.A multicenter study 40 based on 11,466 patients found an increased risk of infection in psoriasis patients under TNF inhibitor therapy.However, Liu et al. 41 reported no difference in SARS-CoV-2 infection, COVID-19 hospitalization in psoriasis patients using IL-17 inhibitor compared to non-biologic agents.In our study, psoriasis treatment modalities were not associated with SARS-CoV-2 infection and COVID-19 hospitalization.Therefore, discontinuing psoriasis treatment is not recommended in the setting of SARS-CoV-2 infection except in the case of a severe COVID-19 event, and active treatment of psoriasis is beneficial in preventing SARS-CoV-2 infection and preventing exacerbation of psoriasis due to SARS-CoV-2 infection.
Although our results indicated that COVID-19 vaccination (including booster dose) in little help in prevention of SARS-CoV-2 infection or reduction of COVID-19 hospitalization.Booster dose vaccination did reduce the incidence of COVID-19 sequelae, the result was similar to a meta-analysis 42 by Gao.Therefore, booster dose vaccination is recommended.This is the pioneer study concerning impact of SARS-CoV-2 infection on psoriasis after the end of dynamic zero-COVID policy in mainland China, in real-world examining effectiveness of COVID-19 vaccine in population with low naturally acquired immunity, and answering the linkage between psoriasis treatment and COVID-19-related events.We also explored the risk factors for exacerbation of psoriasis due to SARS-CoV-2 infection.Because of the high variability of the SARS-CoV-2, another large-scale impact on psoriasis patients is still possible, the findings of our work may contribute to the exploration of psoriasis and SARS-CoV-2 related issues.
There are some limitations of this study.First, regarding the screening of participants, in order to best simulate the situation of SARS-CoV-2 infection at that time, and the limitation of PCR testing and lack of antigen detection kits, we lowered the criteria for confirming SARS-CoV-2 infection to screen as many SARS-CoV-2 infection as possible, which may lead to an increase in the false positive rate.Secondly, despite the fact that the research included three hospitals and some patients were spread throughout many provinces in Southwest China, the majority of them were concentrated in one area.Because some of the patients were elderly and not sure what kind of vaccine they had received, so we did not explore the association between specific vaccine subtypes and SARS-CoV-2 infection.Furthermore, the authenticity of the data may be limited by questionnaires, as psoriasis severity was based on patients' own assessment of BSA.Except that, this survey was completed online, and there might be a selective bias due to the low participation rate of geriatric and pediatric patients.

Conclusion
We found that SARS-CoV-2 infection was associated with COVID-19 vaccination, while booster dose vaccination assisted in lowering the incidence of COVID-19 sequelae.Other major SARS-CoV-2 infection risk factors were female gender, employed individuals, lack of routine protection, severe cases of psoriasis.Associated factors for psoriasis exacerbation were subtypes of psoriasis, response following COVID-19 vaccination, severity of psoriasis, discontinuation of psoriasis treatment.Psoriasis treatment was unrelated to SARS-CoV-2 infection and COVID-19 hospitalization, biologics proved safety during SARS-COV-2 infection.

Figure 1 .
Figure 1.Forest plot for the multivariate regression analysis.In this figure, the position of the circles indicates the adjusted odds ratio (aOR) for each significant factor, and the horizontal lines indicate the 95% CI associated with that value.Y coordinate of the corresponding calibration represents the significant factors associated with SARS-CoV-2 infection.P-value of 0.05 or less are considered statistically significant.

Figure 2 .
Figure 2. Forest plot for the multivariate regression analysis.In this figure, the position of the circles indicates the adjusted odds ratio (aOR) for each significant factor, and the horizontal lines indicate the 95% CI associated with that value.Y coordinate of the corresponding calibration represents the significant factors associated with psoriasis exacerbation.P-value of 0.05 or less are considered statistically significant.